title: Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders.
abstract: A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future.
authors.affiliation: Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Krzewski
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
mesh_terms: D002609:Chediak-Higashi Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016116:Piebaldism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D021381:Protein Transport; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology; D022161:Transport Vesicles / Q000378:metabolism / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D008565:Membrane Proteins; C507969:UNC13D protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins
keywords: Familial Hemophagocytic Lymphohistiocytosis Type 3; Griscelli Syndrome Type 2; Immunodeficiencies; Muc13-4; Rab GTPases; Rab27a